SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1

Yoshioka, Yuichiro; Suzuki, Takehiro; Matsuo, Yo; Nakakido, Makoto; Tsurita, Giichiro; Simone, Cristiano; Watanabe, Toshiaki; Dohmae, Naoshi; Nakamura, Yusuke; Hamamoto, Ryuji

doi:10.18632/oncotarget.11898

Cited by 43 publications

(36 citation statements)

References 58 publications

(66 reference statements)

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“…We and others have reported the important roles of dysregulation of non‐histone protein methylation in carcinogenic processes in various types of human cancer. For example, SMYD3‐mediated AKT methylation at lysine 14 plays pivotal roles in activation of the AKT signaling pathway in breast and colon cancers, and PRMT1‐mediated methylation at arginine 887 of INCENP promotes mitosis of lung and cervical cancers …”

Section: Discussionmentioning

confidence: 99%

“…We and others have reported the important roles of dysregulation of non-histone protein methylation in carcinogenic processes in various types of human cancer. For example, SMYD3-mediated AKT methylation at lysine 14 plays pivotal roles in activation of the AKT signaling pathway in breast and colon cancers, (16) and PRMT1-mediated methylation at arginine 887 of INCENP promotes mitosis of lung and cervical cancers. (39) In the present study, we have shown that SMYD2-mediated methylation of lysine 1610 on the EML4-ALK fusion protein is likely to be critically important for autophosphorylation of some tyrosine residues and the oncogenic activity of the fused proteins.…”

Section: Discussionmentioning

confidence: 99%

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Effects of SMYD2‐mediated EML4‐ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells

et al. 2017

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A specific subtype of non‐small‐cell lung cancer (NSCLC) characterized with an EML4‐ALK fusion gene, which drives constitutive oncogenic activation of anaplastic lymphoma kinase (ALK), shows a good clinical response to ALK inhibitors. We have reported multiple examples implying the biological significance of methylation on non‐histone proteins including oncogenic kinases in human carcinogenesis. Through the process to search substrates for various methyltransferases using an in vitro methyltransferase assay, we found that a lysine methyltransferase, SET and MYND domain‐containing 2 (SMYD2), could methylate lysine residues 1451, 1455, and 1610 in ALK protein. Knockdown of SMYD2 as well as treatment with a SMYD2 inhibitor in two NSCLC cell lines with an EML4‐ALK gene significantly attenuated the phosphorylation levels of the EML4‐ALK protein. Substitutions of each of these three lysine residues to an alanine partially or almost completely diminished in vitro methylation of ALK. In addition, we found that exogenous introduction of EML4‐ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT, one of the downstream oncogenic molecules in the EML4‐ALK pathway, and suppressed the growth of the two cell lines. We further showed that the combination of a SMYD2 inhibitor and an ALK inhibitor additively suppressed the growth of these two NSCLC cells, compared with single‐agent treatment. Our results shed light on a novel mechanism that modulates the kinase activity of the ALK fused gene product and imply that SMYD2‐mediated ALK methylation might be a promising target for development of a novel class of treatment for tumors with the ALK fused gene.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of SMYD2‐mediated EML4‐ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells

et al. 2017

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“…VEGFR1 methylation by SMYD3 augments VEGRF1 kinase activity, which is thought to enhance carcinogenesis [12]. Methylation of AKT1 at lysine 14 is essential for AKT1 activation [13]. In addition, SMYD3 was found to promote formation of inducible regulatory T cells and may be involved in reducing autoimmunity [14,15].…”

Section: Introductionmentioning

confidence: 99%

New open conformation of SMYD3 implicates conformational selection and allostery

et al. 2016

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SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly “closed” substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an “open” conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics. The two states are characterized by many distinct structural and dynamical differences and the conformational transition pathway is mediated by a reversible twisting motion of the C-terminal domain (CTD). The spontaneous transition from the closed to open states suggests two possible, mutually non-exclusive models for SMYD3 functional regulation and the conformational selection mechanism and allostery may regulate the catalytic or ligand binding competence of SMYD3. This study provides an immediate clue to the puzzling role of SMYD3 in epigenetic gene regulation.

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“…For N‐ and C‐terminally EGFP‐tagged Akt1, FLIM showed no variations of fluorescence lifetimes within cells; thus indicating that methylation had no influence on the cellular localization of Akt1. Its methylation sites have been reported to be at Lys14, Lys 30, and Lys39 . Hence, we hoped to observe different FRET efficiencies for EGFP‐Akt1 and Akt1‐EGFP.…”

Section: Resultsmentioning

confidence: 99%

Direct Imaging of Protein‐Specific Methylation in Mammalian Cells

2019

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Abundant post‐translational modification through methylation alters the function, stability, and/or localization of a protein. Malfunctions in post‐translational modification are associated with severe diseases. To unravel protein methylation sites and their biological functions, chemical methylation reporters have been developed. However, until now, their usage was limited to cell lysates. Herein, we present the first generally applicable approach for imaging methylation of individual proteins in human cells, which is based on a combination of chemical reporter strategies, bioorthogonal ligation reactions, and FRET detected by means of fluorescence lifetime imaging microscopy. Through this approach, methylation of histone 4 and the non‐histone proteins tumor suppressor p53, kinase Akt1, and transcription factor Foxo1 in two human cell lines has been successfully imaged. To further demonstrate its potential, the localization‐dependent methylation state of Foxo1 in the cellular context has been visualized.

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SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1

Cited by 43 publications

References 58 publications

Effects of SMYD2‐mediated EML4‐ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells

Effects of SMYD2‐mediated EML4‐ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells

New open conformation of SMYD3 implicates conformational selection and allostery

Direct Imaging of Protein‐Specific Methylation in Mammalian Cells

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